Compositions for use in repairing bone and cartilage by implantation of material comprising a proliferating chondrocyte cell structure having phenotypic capability embedded in a vehicle or gel consisting of thrombin, antiprotease, fibrinogen, extracellular matrix and one or more growth factors that forms a "biological glue" of a biodegradable character are described in U.S. Pat. No. 4,642,120. Before implantation, the cells are grown in tissue culture and harvested, and the chondrocyte population is embedded in the biological glue at a concentration of between from 100,000 to 500,000 cells per milliliter of glue. Before using this formulation, damaged cartilage and bone, as in a hip or other joint, are excised by surgery. A matching implant of the formulation is then inserted in the cavity, with or without bone segments to fill part of the volume. Cell proliferation continues in the permissive environment created by the system, while external influences are restricted. Chondrocytes (cartilage cells) and osteoblasts (bone forming cells) develop to unite with the existing structure, so that after a period of time, the implanted structure is virtually indistinguishable from the surrounding material.
Numerous advantages are derived from this approach in repair of articular cartilage, in comparison, for example, to replacement of a hip joint with a low friction metal-plastic prosthesis. The differences in the biomechanical properties between the bone and the prosthetic element is a major problem. Implantation of a prosthesis disables the mechanoreceptor system in the capsule of the joint which provides feedback for muscle control, resulting in wear and ultimately a need for replacement. The multiple freedoms of motion required of the joint, as for rotational and sliding movement, cannot be provided because of the absence of the mechanoreceptor system. In addition, the best low friction prosthetics have over 100 times the friction of the natural cartilage structure with the intervening synovial fluid, and for this reason also, wear and degradation are inevitable.
While the composition of U.S. Pat. No. 4,642,120 has a demonstrated potential for repair of articular cartilage, it also has been recognized to have a number of limitations as a result of further experimental work. The needed cell proliferation capability was thought to be best available in embryonal chondrocytes (young committed chondrocytes) but for human use, availability is limited and major problems can arise from immune system reactions. Bone marrow stem cells are merely mentioned in the patent as a different possible source of cells, along with mesenchyme cells having potentiality for conversion to cartilage cells by self differentiation or under the direction of chondrogenic factors. No work was done using these progenitors. Additional detailed information and discussion is contained in an article entitled "Use of Cultured Chick Epiphyseal Chondrocytes as Grafts for Defects in Chick Articular Cartilage", by S. Itay et al, Clinical Orthopedics, pp. 284-302, July, 1987.
The article mentioned cites a number of articles of general relevance to the topic as a whole. Three of these are of particular interest because they evidence attempts to transplant chondrocytes into articular cartilage that encountered limited success because, at least in part, of the absence of suitable biodegradable viscoelastic material and inability to produce cartilage. The three articles are: Bentley, G. et al, "Homotransplantation of isolated epiphyseal and articular cartilage chondrocytes onto joint surfaces of rabbits", Nature 230:385 (1971); Bentley, G. et al, "Isolated Epiphyseal chondrocyte allograft onto joint surface--An experimental study in rabbits", Ann. Rheum. Dis. 37:449 (1978); and Helbing, G. et al, "In vitro Untersuchungen an isolierten Chondrozyten zur Prognose von Knorpeltransplanten", Helv. Chir. Acta 46:21 (1979).
As pointed out in U.S. Pat. No. 4,642,120, it was previously thought that a limit had to be observed for chondrocyte concentrations of about 500,000 cells per milliliter of gel in order to avoid necrosis of the cells. Also, it was thought that only 5-50 units of thrombin per milliliter and about 25-80 mg/ml fibrinogen should be employed, with the setting of the gel being determined by the level of the thrombin, which should be kept at a limit of less than 50 units/ml. These relationships and parameters were found on further studies to limit proliferation rates and capacities, and capability for maturation and transformation of the implant into suitable phenotypic expressions, especially in large defects. Consequently, extension of this approach to repair of articular cartilage necessitates new compositions and procedures.